Ever since the discovery and isolation of LAV by Barre-Sinousi, Chermann and Montagnier in 1983 at the Pasteur Institute a search for effective treatment without major side effects and prevention of AIDS has been elusive.
Treating patients with AIDS with a combination of reverse transcriptase and drugs that target HIV's protease enzyme, known in the art as “highly active antiretroviral therapy,” is effective to drive the viral load in blood to low levels.
Thus, since 1996, antiretroviral drugs such as zidovudine (AZT), ritonavir, saquinavir, lamivudine, amprenavir, abacavir, idinavir, nelfinavir and the like, were generally used in triple-drug therapy using two reverse transcriptase inhibitors and one protease inhibitor, to reduce the amount of HIV in patients. However, none of these drugs entirely eliminates the virus.
Moreover, there remains serious problems associate with the triple-drug therapy. Not only must an HIV-infected person take the drugs on a consistent schedule and for the duration of life, but these drugs are not only quite expensive ($10,000 annually or more), but toxic. Due to their toxic nature, antiretroviral drugs have known side effects which include nausea, vomiting, diarrhea, anemia, lipodystrophy, diabetes-like problems, brittle bones, numbness, tingling or pain in the hands or feet, and heart disease. As a result of these side effects many AIDS patients stop taking their medication.
Besides their toxic effects, one of the major difficulties with highly active retroviral therapy is drug resistance. Since HIV is known to constantly mutate, billions of new HIV viruses are produced in the body every day. These mutations change parts of the virus often rendering the drugs ineffective. The alternative to antiretroviral drugs would be to develop an effective vaccine against HIV.
It is now widely believed that a successful HIV vaccine preparation should have components to stimulate T-cell responses and to elicit anti-HIV antibodies. Currently more than 25 HIV vaccines designed to stimulate T-cell responses are in clinical trials, whereas no vaccine that is capable of stimulating the production of broadly neutralizing antibodies and/or antibodies that inhibit infection by primary isolates of HIV-1 has yet been described. Thus the design of a vaccine capable of stimulating neutralizing antibodies that inhibit primary HIV isolates appears to be one of the highest priorities in the HIV vaccine research (McMichael, 2006; Zwick and Burton, 2007).
The external envelope glycoprotein gp120 has widely been investigated for the development of neutralizing antibodies. However such antibodies are isolate specific due to the sequence variability of gp120 and thus have a limited action; in particular they fail to neutralize primary isolates. Alternative strategies are now being evaluated for the stimulation of neutralizing antibodies against the receptor, coreceptor binding sites and also cryptic epitopes that may become exposed following the binding of gp120 to CD4 (Lin and Nara, 2007; McMichael and Hanke, 2003). In contrast to gp120, the transmembrane envelope glycoprotein gp41 provides a good alternative glycoprotein to explore by virtue of the conserved domains. However, the problem in this case is that the strategic epitopes might be covered by gp120 and/or are thought to be cryptic epitopes (Wyatt and Sodroski, 1998). An exception is the C-terminal half of the gp41 ectodomain harboring the epitopes of neutralizing human antibodies 2F5 and 4E10. Subunits of gp41 have been considered as candidates for a vaccine; however, antibodies raised against the N-HR and C-HR regions were shown to be non-neutralizing under physiological conditions. Similarly, all attempts to induce neutralizing antibodies against the epitope of neutralizing human monoclonal antibodies 2F5 and 4E10 have failed (Lin and Nara, 2007; Zwick and Burton, 2007).
A strategic epitope in the HIV-1 transmembrane envelope glycoprotein gp41 that is conserved in every single HIV-isolate has been identified (Hovanessian et al., 2003, 2004a; Hovanessian et al., 2004b). Synthetic peptides corresponding to this epitope (named the CBD1 epitope) were then shown to elicit reproducibly in rabbits the production of antibodies that inhibit HIV-1 infection of primary CD4+ T lymphocytes by various T lymphocyte and macrophage-tropic HIV-1 isolates and as well as primary isolates of clades A to G. Viral particles preincubated with the immune sera loose their infectivity, while addition of the immune sera to virus producing cultures results in the production of defective virus particles (Hovanessian et al., 2004b). The caveolin-binding domain therefore is exposed on HIV particles and also on virus-infected cells. The anti-CBD1 antibodies act on two distinct steps on the HIV-infectious cycle: 1) they prevent infection of cells by HIV particles; and 2) they cause aggregation of gp41 at the plasma membrane in HIV-producing cells leading to the production of virus particles deficient in the gp120-gp41 complex.
A highly conserved B cell-epitope, the CBD1 epitope, in the ectodomain of HIV-1 gp41, and the capacity of peptides corresponding to this epitope to elicit the production of antibodies that inhibit various HIV-1 isolates, provided promising perspectives for the development of synthetic universal B-cell epitope vaccine candidate for HIV/AIDS (Hovanessian et al., 2003, 2004a; Hovanessian et at., 2004b).
However, improved HIV-1 vaccines that provide better immunogenic protection is still needed.
Thus it is an object of the present invention to provide a composition and more specifically an immunogenic composition that induces broadly neutralizing activities and/or antibodies that inhibit infection by primary isolates of HIV-1.
It is another object of the present invention to provide a universal B-cell epitope vaccine capable of eliciting in a mammal the induction of HIV-specific broadly reactive neutralizing antibodies.
It is yet another object of the present invention to provide vaccines which contain highly purified peptides that can be made in larger quantities and at lower costs.
Yet another object of the present invention provides immunogenic compositions with fewer side effects that broadly elicit neutralizing antibodies because of their conserved nature among various HIV-1 isolates and clades.
Still yet another object of the present invention is to provide immunogenic compositions or vaccine preparations that have application as a therapeutic vaccine in HIV-infected individuals, since HIV-infected individuals appear to lack the capacity to produce naturally anti-CBD1 antibodies.
Another object of the present invention is to provide a chimeric peptide or chimeric proteins that can be used in compositions, pharmaceutical compositions, immunogenic compositions and as vaccines.
Antibodies and especially monoclonal antibodies directed to the described peptides and chimeric peptides is another object of the invention.
Still another object of the present invention is to provide a method of neutralizing HIV-1, said method comprising administering to a mammal in need of such treatment at least one chimeric peptide of the present invention. Also disclosed is at least one chimeric peptide of the invention for use in neutralizing HIV-1.
Yet another object of the present invention is a method to induce antibodies able to neutralize HIV-1, said method comprising administering to a mammal in need of such treatment at least one peptide of the present invention with at least one peptide containing a T helper epitope.
Use of at least one chimeric peptide described in the present invention for the manufacture of a medicament to induce neutralizing antibodies against HIV-1 is yet another object of the invention.
Yet another object of the present invention is the use of at least one chimeric peptide for prophylaxis for HIV-1 infection.
These and other aspects and objects are achieved by the present invention as evidenced by the summary of the invention, description of the preferred embodiments and the claims.